Process of percutaneously administering exact doses of physiologically active agents and composite unit therefor



Sept. ll, 1962 F. MEYER 3,053,255

PRocEss oF PERcUTANEousLY ADMINISTERING EXACT DOSES 0F PHYSIOLOGICALLY ACTIVE AGENTS AND COMPOSITE UNIT THEREFOR Filed Deo. 1e, 1958 5 2O 40 60 NIN. INVENTOR.

@160Q/cl! Mn-4Q 3,053,255 PROCESS F FERCU'lANEOUSLY ADMlNlSTER- ING EXACT DOSES 0F PHYSIOLOGICALLY AC- TIVE AGENTS AND COMPGSITE UNIT THERE- FOR Friedrich Meyer, Schoenenfelder Str. 20, Hamburg- Wilhelmsburg, Germany Filed Dec. 16, 1958, Ser. No. 780,795

Claims priority, application Germany Dec. 19, 1957 7 Claims. (Cl. 12S- 268) The present invention relates to an article of manufacture and a process for dispensing dosed quantities of physiologically active material for percutaneous absorption.

The application of salves, ointments, liniments, powders, which may contain pastes, cerates, or other externally applicable preparations of physiologically active agents to the outer skin surface has been employed by the medical `profession and in the cosmetic arts for a long time. This mode of application may have for its purpose to bring about a topical eect, for instance, it may cause local disinfection or it may be intended for a far-reaching absorption effect extending also to other parts of the body than those Where the preparation has been applied topically, such as, for instance, the long known treatment with a mercurial ointment, i.e. with unguentum hydrargyri, used in the treatment of syphilis.

There are numerous other examples of the topical application of medication for local eifect but only comparatively few examples for systemic action. The reason `for this is that it is quite easy to topically apply to the skin in this manner a definite quantity of a liquid, a powder, an ointment, a jelly, or the like preparation. Yet in most cases it is not possible to determine how `much of the medication has been taken up by the organism through absorption or whether it only superlicially penetrated the skin. Furthermore, it is also usually not pos- `sible to `determine how much of the preparation has evaporated or how much of it remains on the skin as nonpenetrating residue.

Up to the present time it was not possible to regulate and control the percutaneous absorption of a specific material, i.e. to cause a definite quantity of material (an exact dose) to be absorbed. Examples of uncontrolled ,percutaneous absorption have occurred with ointments containing salicylic acid, which ointments may cause serious toxic effects and even death through poisoning. However, in a few cases, percutaneous dispensing of toidcologically relatively harmless active agents have proven to be more or less effective, for instance, in the treatment with hormone preparations.

In general it can be stated that the lack of a method of percutaneously administering a precise dose of a therapeutically active agent to be absorbed by the skin had the result that percutaneous administration of such physiologically active agents found only limited use in medical practice. This is so, notwithstanding the pressing need for a method of administration of this type and for means for carrying out such a method. This need is evidenced by numerous publications concerning skin permeability. See, for instance, Die Durchlaessigkeit der Haut fuer Arzneien und Gifte (in translation: The permeability of the skin for drugs and poisons), Berlin, 1942, by E. Buergi, who is one of the foremost toxicologists. Similarly, from more recent publications, for instance, of G. Hadgraft and F. Somers in 1. Pharm. Pharmacol, vol. 6, page 944 (1954); and G. Hadgraft, F. Somers, and H. S. Williams in I. Pharm. Pharmacol, vol. 8, page 1027 (1956); as well as of Gemmell and Morrison in 1. Pharm. Pharmacol, vol. 9, page 641 (1957), two things clearly emerge:

(l) The extensive protective and defense function of human skintoward outside chemical inuences.

3,053,255 Patented Sept. 1l, 1952 fic (2) The extensive and practical interest in the percutaneous dispensing of therapeutically active agents (compare, for instance, Czetsch-Lindenwald and Schmidt-La Baume, 1950, Heidelberg: Salben, Puder, Externa, die aeusseren Heilmittel der Medizin (in translation: Ointments, powders, external agents, the external remedies in medicine), 3rd edition, Berlin-Gottingen-Heidelberg, 1950. One condition of suc'h percutaneous administration is, that a denite and as complete an absorption as possible as well as administration of the required dosage can be achieved.

It is one object of the present invention to provide a new and highly advantageous method of percutaneously administering definite doses of physiologically active agents.

Itis a further object of this invention to provide a device or assembly for effecting this purpose.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

The new process according to the present invention, which Will be described more in detail hereinafter and which permits the administration of therapeutically or cosmetically active agents through the skin, has made possible a number of Substantial advantages:

(1) Active agents, which normally Iare not absorbed by the skin or are only taken up sparingly, are now rendered readily absorbable.

(2) The percutaneous absorption of active agents, which normally penetrate the skin only in small quantities, or only slowly from conventional preparations such as ointments, jellies, or solutions (for instance, containing salicyclic acid, iodine, or hormones), is definitely promoted or accelerated. v

(3) Percutaneous absorption becomes readily controllable and can be adjusted so that it is practically complete.

(4) Percutaneous absorption of the active agent can be exactly dosed.

These advantages permit in many cases percutaneous administration of active agents, which heretofore could be administered only parenterally. Both methods of administration can now be used equally well. Itis, of course, ,understood that percutaneous application according to the present invention cannot replace all forms of parenteral administration. For instance, it cannot replace administration by intravenous injection when the introduction of the active agent by this route is necessary in order to `cause rapid action of the active drug. Likewise it cannot replace administration by injection into the cerebrospinal uid in the spinal canal.

The process according to the present invention shows the following advantages over the usual forms of injection,

i.e. over subcutaneous, intracutaneous, intramuscular, and

even over intravenous injections:

(a) Less annoyance for the patient since the pain of injection is absent;

(b) Less danger of infection;

(c) More convenient handling for the physician, since sterilization of syringes and needles is dispensed with.

The new process according to the present invention has the `further particular advantage that it permits non-disturbing, convenient, and at the same time safe administration `of such active agents which on oral administration are partially or totally destroyed in the gastro-intestinal tract, or which for other reasons are not absorbed quickly enough or completely enough. Such agents are, for instance, curare, strophanthin, convallatoxin, adrenalin, acetyl choline, or agents which are badly tolerated on oral administration, such as saponin containing drug extracts.

The process according to the present invention makes it further possible to vary within wide limits the rate of absorption of active agents. Heretofore such variation in 9 the rate of absorption could be achieved only by enteral administration through the gastro-intestinal tract or parenterally by way of injection.

In principle the process according tothe present invention consists in first applying to an absorptive carrier material a measured quantity (dose) of the active agent to be absorbed by the skin. This absorptive carrier material is covered with a non-absorptive, non-permeable separator material. A second layer of absorptive material serving as the reservoir for the active agent is placed on top of said separator layer. This reservoir layer is somewhat thicker than the carrier layer. One or several wicks of absorptive material are provided to make a connection between the reservoir layer and the carrier layer. In use a liquid vehicle supplied to the reservoir layer is carried through the wicks to the carrier layer wherein it picks up the active agent and causes it to be absorbed by and through the skin in a definite predetermined dose.

The manner in which the process according to the present invention is carried out and the means used thereby will become apparent from the following description and the annexed drawings.

In said drawings:

FIG. 1 is a top plan View of a plaster-like preparation embodied in the present invention;

FIG. 2 is a cross-sectional view taken along line 2--2 of FIG. l;

FIG. 3 is a cross-sectional View taken along line 3-3 of FIG. 2;

FIG. 4 is a cross-sectional View of another embodiment of the present invention; and

FIG. 5 illustrates curves showing the anesthesizing effect of a preparation according to the present invention.

In accordance with the present invention an active agent, which is to be absorbed by the skin, is measured out (by volume or by weight) in solid form, for instance, 0.1 mg. of gor k-strophanthin, or in liquid form, for instance, 0.04 cc. of an 0.25% alcoholic solution of gstrophanthin, and is applied to an absorptive carrier for the active agent, for instance, paper, cellulose, silk, linen, nylon, and other artiicial fiber tissue, and the like material. The carrier material impregnated with a measured predetermined amount of active agent may then be applied to the skin before or after completing the assembly of the parts of the preparation used in the present invention. This carrier material impregnated with active agent is then covered with a non-absorbent, non-permeable -separator material having about the same surface area as the carrier material. The separator material may consist, for instance of a film or foil of 0.1 mm. to 0.5 mm. thickness and made of rubber, wax paper, a substantially liquid impermeable synthetic resin, such as polyvinyl chloride, and the like. This separator material is preferably provided with one or more openings which have as their purpose to receive the wicks described more in detail hereinafter. Upon the non-permeable separator material there is placed the reservoir material. This reservoir material consists of a layer of absorbent fibrous material, such as cotton, paper, cellulose, linen, silk, nylon, or other natural or synthetic iber material, and serves to take up the solvent, the function of which is also described hereinbelow. This reservoir has also about the same surface area as the carrier layer. However, it is thicker than the latter and has a thickness, for instance, of several mm. The reservoir has sufiicient capacity to take up, for instance, from 0.5 cc. to 1 cc. of a suitable solvent or solvent mixture which is free of active agent. This solvent functions as a guide rail i.e., it causes the active agent to be absorbed by the skin by dissolving it out of the `active agent carrier. The solvent and the active agent dissolved therein together penetrate the skin. Therefore, the solvents are called transporting substances or vehicles The vehicle oWs out of the reservoir carrier to the active agent carrier by means of one or more wicks which are made from absorbent materials, such as paper, Wool, cotton, cellulose, silk, linen, nylon, or other synthetic fibers, and the like. The Wick can be in the form of filaments, for instance, Wool laments, or in the form of bands, for instance, paper strips. These wicks connect the reservoir carrier with the active agent carrier. It is understood that the cross-sectional area of all the Wicks together must be such that at least so much of the vehicle can flow therethrough (including the active agent dissolved therein) as will be absorbed by the skin from the active agent carrier. The aggregate cross-sectional area of the wicks will vary with the size of the skin surface area covered. Thus, for instance, if the carrier has an area of 40 sq. cm., the aggregate crosssectional area of the Wicks will be larger than in the case where the carrier has a surface area of 4 sq. cm. The wicks can be conducted from the reservoir carrier to the active agent carrier either around the separator layer, in the case where no perforations are provided in said separator layer, or through perforations in the separator layer.

Referring to FIG. 2 of the drawings which is illustrative of the present invention, an adhesive plaster strip 1 is secured to covering 2 made of non-absorbent, substantially liquid and gas impermeable material which is flexible or non-exi'ble, consisting, for instance, of plastic foil, such as polyvinyl chloride film, lacquer, rubber, glass, or other suitable materials. This cover 2 serves to prevent evaporation of the vehicle and/ or to keep out the oxygen of the air, if readily oxidizable active agents and/or vehicles `are employed. Disposed right beneath cover 2 is reservoir carrier 6 which, as mentioned above, may be of cotton, paper, cellulose, silk, linen, nylon, or other synthetic fiber material. Located beneath reservoir carrier 6 is separator layer 3 which separates reservoir carrier 6 from active agent carrier 4. In this embodiment of FIG. 2 the separator layer 3 is not perforated and active agent carrier 4 is in communication with reservoir carrier `6 through wick 5, which is drawn around the edge of separator layer 3. In this figure carrier 4 may have `an area of 4 sq. cm. and is 0.2 mm. thick. The surface area of the other layers, such as of reservoir layer 6 and separator layer 3 are of substantially the same size. A protective strip 7 of any suitable material is provided to protect the carrier 4 from being soiled and to prevent evaporation of the solvent and/or active agent before use and on storage.

The Various elements as shown in FIG. 2 and described hereinafter, namely active agent carrier 4, separator layer 3, reservoir carrier 6, wicks 5, cover 2, adhesive plaster strip 1, and protective strip 7, are combined into a convenient unit or article of manufacture for carrying out the process according to the present invention. The size and the form of the various elements may be varied and adopted for various uses. For instance, in dispensing strophanthin, the normal dose of which is very small for humans and lies between 0.1 mg. to 0.2 mg., a carrier 4 having a small surface area of 4 sq. cm. is used. In this case wicks 5 of paper strips 2 cm. wide are employed, which are conducted around the edges of separator layer 3. A suitable reservoir carrier 6 is used which has an area of 4 sq. cm. and is l mm. to 2 mm. thick and made of a layer of cotton having a capacity of about 0.5 cc. to 1 cc. for the transport substance or vehicle.

In using the unit according to the present invention, a definite quantity of active agent or a solution thereof is placed on carrier 4 which is prefer-ably colored to distinguish it from the other layers. 'Ihe vehicle is then introduced in any suitable manner into the reservoir carrier 6 in the desired quantities according to the directions of use. The finally assembled unit of the various elements shown in FIG. 2 is then placed on the skin and secured thereto by a bandage, a strip of adhesive tape, or an adhesive film. The assembly can also be made so that carrier 4 is previously loaded with the necessary dose of active agent. In this case the user need only then apply the transport substance or vehicle to the reservoir carrier 6, for instance, by a pipette, either before or after the assembly is secured to the skin. The assembly can also be provided with means secured to it for fastening it to the skin, such as with an adhesive strip. In this case the carrier 4 with active `agent and the adhesive layer 1 are protected from becoming dirty by a common protective layer 7 which is separated before use.

In the modification of this invention as shown in FIG. 4 an arrangement is provided whereby a complete unit is supplied containing both the active agent carrier 4 impregnated with active agent and vehicle contained in the reservoir carrier 6. This arrangement is made possible through the use of a non-permeable coniining or blocking layer 8 consisting, for instance, of a hlm otE polyvinyl chloride or the like liquid impermeable plastic material which serves to prevent putting into operation diiiusion of the transport substance or vehicle through the wicks 5 into the active agent carrier 4 and dissolution of the ractive agent present in carrier 4. In use of this modication of the invention the assembled unit is placed on the skin and then blocking layer 8 is removed or torn, for instance, by pulling itv out sidewardly. 'By this operation wick 5 is brought into communication with reservoir 6 whereby the vehicle contained in the reservoir is conveyed to the carrier 4 and functions as described above. The transport substances or vehicles that may be used in accordance with the present invention are liquids which must meet the following requirements:

(1) They must be suiciently absorbable through the unbroken skin.

(2) They must have suiiicient dissolving power for the active agent which is to be brought in contact with the skin for absorption.

(3) They must be toxicologically unobjectionable for the tskin or the whole organism.

The following transport substances or vehicles are particularly suitable for the purpose of the present invention:

(a) Monoor polyvalent primary, secondary, or tertiary aliphatic, cycloaliphatic, or aromatic alcohols containing 2 to lO carbon atoms, such as hexanol, cyclohexanol, benzyl alcohol, butanediol-(LZ), glycerol; secondary or tertiary amyl alcohol, 3-hexanol-l;

(b) Aliphatic, cycloaliphatic, or aromatic hydrocar- Ibons having 5 to 12 carbon atoms, such as n-hexane,

ride, n-hexyl bromide, cyclohexyl chloride.

The low molecular compounds of this group, such as dibromo ethane, trichloroethylene, are less suitable because of their low compatibility; however, they may be used in mixtures with other vehicles;

(g) Mixtures of substances under (a) to given above.

The following examples are further illustrative of the present invention. However, it is to be understood that this invention is not restricted thereto.

Example l To an active agent carrier 4 of the unit illustrated in FIG. 3, which consists of silk strips having a surface area of 2 sq. om., there are applied 0.02 mg. of eserine base dissolved in 10.02 cc. of ethyl alcohol. The alcohol is of the assembled unit according to the present invention.

1/2 cycle per second, 2.5 m./sec. and 8 ma.

then evaporated leaving carrier 4 uniformly impregnated with said eserine base. 'Ihe active agent carrier is then covered with separator lstrip 3, consisting of a polyvinyl chloride iilm of 0.2 mm. thickness and having three perforations, one of them indicated at 9. On said separator strip 3 there is placed a reservoir 6 consisting of a cellulose layer 3 mm. thick which is connected with carrier layer 4 by three wicks 5 (silk liilaments 0.3 mm. thick) `which pass through the perforations 9` in separator layer 3. The reservoir layer 6 is provided with 0.3 cc. of a vehicle mixture of amyl alcohol, n-hexanol, and cyclohexane in the proportion of 10:25 :65.

The following pharmacological tests were carried out to show the advantageous eiect of such a unit preparation in comparison with a conventional 1% eserine ointment.

Three of these assembled units are secured to shaved abdominal skin of 3 male mice having a body weight of from 18 g. to 20 g. with the aid of cover 2 and conventional adhesive tape strips 1. Within 30 minutes Vafter application the known eserine etl'ect on the striated muscles due to absorption of eserine is detected. There results an increase in chewing movement on periodic stimulation of the chewing musculature (masseter musole) by constant, reactangular electric current impulses of (For the method compare F. Eichholtz, R. Hotovy, and H. Erdniss; Arch int. pharmacodyn. vol. (1949), page 62.) Thirty minutes after the onset of the eserine effect, the assembly is taken oli and the non-absorbed residue on carrier 4 is determined according to the method described by F. Meyer in Arzneimittelforschuug vol. 1, page l(1951). Despite the sensitivity of this chemical analytical method, eserine is no longer detectable.

0.5 g. each of conventional eserine ointments containing 1% of eserine are applied to 4 sq. cm. ofthe shaved Vabdominal skin of two groups of 3 mice each. Unguentum molleV (German Pharmacopeia, 6th edition, 1947 printing of the Arbeitsgemeinschaft Medizinischer Verlage G.m.b.H. of Berlin), i.e. an ointment consisting of 'one part of yellow Vpetrolatum and one part of lanoline is used as ointment base for the -iirst group of mice, while unguentum cereum (German Pharmacopeia 6th Vedition etc.) consisting of 7 parts of ,peanut oil and 3 parts of yellow waxA is used as ointment for the second group of mice. No eserine effect could be recorded with all six experimental animals on observation for 2 hours, although an amount of eserine is applied to the skin which is about 250 times as large as that applied by means Example 2 Yeter) 8 silk iilaments S of 0.3 mm. thickness were pulled.

Said filaments 5 serve to form the Wicks connecting reservoir V6 and carrier 4. AV cellulose layer 0.5 cm. thick and having an area of 4 sq. cm. serves as reservoir 6. It is supplied and impregnated with 1 cc. of a vehicle liquid consisting of cyclohexanone, ethylene glycol, hexanol, and cyclohexane in the proportion of l0:10:-50:30. The outside covering 2 is provided by a flexible polyvinyl chloride iilm having an area of 9 sq. cm.,which is secured to the abdominal skin by means of a muslin bandage. All three animals show 30 to 45 minutes after application the typical, reversible poisoning eiects of strophanthin, such as muscular tremor, convulsions, and respiratory impairment. The assembly is removed after 50 minutes. The

non-absorbed residue on carrier 4 is determined with the aid of the color reaction agent described by Kedde as cited by J. E. Bush and D. A. H. Taylor in Biochem 1., vol. 52 page 643 (1952). This reagent consists of 3,5- dinitro benzoic acid in alcoholic potassium hydroxide. The test results were only weakly positive as indicated by a slight rose coloration indicating the presence of traces of strophanthin, i.e. less than 0.005 mg. to 0.015 mg. approximately uniformly distributed over carrier 4. The same dose of 0.1 mg. of g-strophanthin, and even a dose of 1 mg. of strophanthin administered orally or, respectively, cutaneously in the form of an ointment has no noticeable effect.

Example 3 Three guinea pigs having a body weight between 380 g. and 400 g. receive 0.1 mg. of g-strophanthine by the aid of a unit preparation ready for use according to this invention. The unit is applied to the shaved abdominal skin of the animals. The active agent carrier 4 and the two wicks 5 (FIG. 4) consist of filter paper strips 2 cm. wide and 6 cm. long (Schleicher & Schuell lter paper No. 2043b). An area of 2 cm. by 2 cm. (4 sq. cm.) in the middle of these strips serves as active agent carrier 4. 0.1 mg. of g-strophanthin dissolved in 0.04 cc. of ethanol are applied to the carrier. Both ends of the strips (likewise 2 cm. x 2 cm.) serve as band forming wicks 5. They are passed around separator strip 3 having an area of 4 sq. cm. and consisting of a non-perforated film of polyvinyl chloride having a thickness of 0.1 mm. as shown in FIG. 4. A layer of pressed cotton 3 mm. thick and having an area of 4 sq. cm. serves as reservoir carrier 6. Said layer is impregnated with 1 cc. of the transporting liquid or vehicle mentioned in Example 2, i.e. with a mixture of cyclohexanone, ethylene glycol, hexanol, and cyclohexane in the proportion 10:10:5030. The outside covering 2 consists of a flexible polyvinyl chloride film showing an area of 9 sq. cm. The edges 1 of said cover 2 are provided on their underside with an adhesive so that they form an adhesive tape which serves to secure the assembly to the skin. A blocking layer 8 is arranged between the reservoir 6 and the wick and carrier zone. Said blocking layer 8 consists of polyvinyl chloride. It is secured at its margins to the outer covering Z and is removed before using the unit so that reservoir 6 communicates with wicks 5.

Within 45 minutes after the application of such a unit to the `skin of the three experimental animals there are observed in all the animals the reversible poisoning etects described in Example 2. Analysis of the residue in the carrier in accordance with the Kedde method described hereinabove shows a diiference from the results obtained in Example 2. Non-absorbed residue is found only in the middle of the carrier in an ill defined band of about 2 mm. to 3 mm. width. This finding clearly demonstrates the functioning of the wicks, which are passed around the separator layer 3. They permit the vehicle liquid to flow into the carrier from the two sides, i.e. from the outer portion toward the center.

Example 4 Two-groups each of three guinea pigs receive 0.1 mg. of g-strophanthin using a unit ready for use and applying said unit to the shaved abdominal skin of the animals. The same conditions as used in Example 3 are employed. The only ditference is that the vehicle liquid of Examples 2 and 3 is replaced by the same volume of two different mixtures.

With the rst group of three animals there is employed a mixture of cyclohexanone, ethylene glycol, n-hexanol, and cyclohexane as -used in Examples 2 and 3, but in other proportions, namely in the proportion of 5 :15 :70:10. With the second group of three animals a mixture of ethylene glycol and n-hexanol in the proportion of 70:30A is employed.

In contrast to the results achieved with the vehicles of Examples 2 and 3, wherein within 45 minutes after application of the unit according to the present invention the characteristic poisoning effects of strophanthin are observed, the results in these experiments are different. With the first group of animals (transporting liquid: cyclohexanone, ethylene glycol, n-hexanol, cyclohexane in the proportion 5 :l5 :70:10) the above described toxic etfects are observed only 3 hours after administration. With the second group of animals (transporting liquid: ethylene glycol and n-hexanol in the proportion of 70:30) the assembly is left on the skin for 20' hours without the slightest toxic effects being observed. After the expiration of such a period of observation of almost one day, the three units are removed and the amount of nonabsorbed residue on the carrier is determined. Chemical analysis according to Keddes method was negative. All of the active agent was absorbed (very slowly).

It is evident from these observations that the speed of percutaneous absorption of an active agent Afrom an assembly according to the present invention can be varied within wide limits by varying the composition of the transporting liquid or vehicle.

Example 5 For many purposes itis important to determine whether the quantity of therapeutically active agent applied has been completely taken up by the blood stream, i.e. to ind out whether part of the active agent has been retained by the superficial skin layers. I-f this were the case, the active agent, for instance, the strophanthin, would also not have been detected in the residue on the carrier. The following experiments show that a measured quantity of g-strophanthin, administered according to the present invention, is quantitatively absorbed in the blood stream. As the small therapeutic doses of 0.1 mg. of strophanthin, as they are conventionally administered, cannot be detected with certainty by chemical analysis in the blood, faeces, or the organs, biological methods must be used to find out how much of the strophanthin has entered the blood stream. `In these experiments a predetermined quantity of g-strophanthin, such as one half of the lethal dose of intravaneous in- -fusion is applied to the skin. That this amount is quantitatively absorbed and has entered the blood stream can readily be ascertained by subsequently injecting intravenously the other half of the lethal dose. If all the animals are killed, it is obvious that all the strophanthin administered precutaneously must have been absorbed through the skin into the blood stream.

For this purpose fifteen guinea pigs (under urethane anesthesia 2 g./kg. of body weight) are given by intravenous infusion lethal doses of g-strophanthin used in the further experiments. rIlhe lethal dose amounts to 0.31 mg./kg.i0.048 rug/kg. at a speed of infusion of 0.0047 mg./min. To ten other animals similarly anesthesized with urethane, there was administered half the lethal dose, i.e. 0.15 mg. of g-strophanthin per kg. body weight by means of a 4 sq. c-m. `carrier applied to the skin in accordance Iwith the procedure of Example 3. The assembly is allowed to remain on the skin -for minutes under the conditions of Example 3, to cause absorption of the active agent. Thereafter it was determined which amount of strophanthin intravenously injected, causes death of the thus pretreated animals. It was found that 0.18 mg./kg.i0.08 mg./kg. are required to kill the animals. Thus the sum of the amount of active agent absorbed precutaneously I(0.15 nig/kg.) and that required to kill the animals on intravenous administration (0.18 mg./kg.i0.08 rng/kg.) corresponds approximately to the previously determined lethal dose of 0.31 mg./kg. Since the test with the residue on the l0 carriers according to Keddes reaction was negative, it has been proved that the quantity of active agent applied to the skin practically completely entered the blood stream. The present process not only permits absorption of toxic 9 doses but also permits precutaneous absorption of exact, small, therapeutically effective doses.

In the same manner as described above in connection with g-strophanthin, other cardio-active glycoides, such as k-strophanthin and convallatoxine, various alkaloids such as morphine and strychnine as well as barbiturates, such as phenyl ethyl barbituric acid can be administered percutaneously in therapeutic as well as toxic doses.

Example 6 Five guinea pigs receive 0.04 cc. of a 10% solution of procaine in base form in n-hexanol with the aid of a 4 sq. cm. carrier 4 made of linen tissue. These carriers are applied to the shaved abdominal skin in the same manner as described in Example l. Separation layer 3 is placed over the carrier 4 also measuring 2 cm. x 2 cm. It consists of a exible polyvinyl chloride iilm which is provided with 25 round openings of 0.2 mm. diameter. Silk iilament wicks 5 are passed through each of these openings. The wicks 5 communicate with the superposed reservoir 6. Said reservoir is m-ade of a 3 mm. thick layer of cotton having a surface area of 4 sq. cm. The reservoir 6 contains 1 cc. of a transporting liquid or vehicle consisting of hexanol and cyclohexane in the proportion of 1:4. After allowing the unit to rem-ain on the skin for 45 minutes, percutaneous absorption of the procaine is determined by its pain Ikilling elect. Whether anesthesia is achieved, is determined by exposing the animals to niechanical irritation or, respectively, to electrical irritation by means of rectangular electrical impulses of 30 cycles per see. and a duration of 1 msec. with variations in current intensity of from 0.2 ma. to 2.5 ma. and determining the dose required to suppress pain reaction ofthe animals.

Example 7 Two volunteers are used in the following experiment. 1 mg. of procaine per sq. em. of skin surface is applied to the untreated skin of the back of the left hand of each of the persons, whereby the conditions of Example 6 are observed. After 40 minutes a very definite anesthetic eff fect sets in. The intensity of electrical stimulation can be raised many times until pain reaction sets in. While the normal stimulus threshold is attained by the application of impulses of 0.2 ma. to *.3 ma., percutaneous treatment with procaine according to the present invention raises said threshold to about 2 ma, before pain sets in. The unbroken curve illustrated in FIG. shows said anesthesizing effect which subsided only very slowly, i.e. within 60 minutes.

Example 8 The volunteers used in the experiment of Example 7 receive, by application to the back of the hand, under the conditions described in Examples 6 and 7, 1 mg. of procaine per sq. cm. of skin surface and, in addition thereto, 1 mg. of Z-(u-naphthyl methyl) imidazoline nitrate sold under the trademark Pri-vin by Ciba A. G. of Basel, Switzerland. Said imidazoline compound was also present in the active agent carrier 4 containing the pro- 60 like procaine in the skin for a prolonged period of time 70 or to attain =a higher concentration of the active agent in the skin by the addition of a vasoconstrictor drug.

If, on the other hand, nicotinic acid amide or nicotinic acid methyl ester, each of which is a vasodilator, are

10 of skin, the duration of action is shortened, as is evident from the dotted curve in CFIG. 5.

The results described hereinabove in the examples have been confirmed in actual clinical use, for instance, with cardiac patients to whom strophanthin was administered, with patients suffering, for instance, from intestinal distention or paresis to whom escerine was administered, with patients to be exposed to the action of local anesthetics, such as procaine, with patients under morphine, for producing sedative and hypnotic elects, for instance, by administration of barbiturates, and others.

Of course, many changes and variations in the composition and size of the active agent carrier, the separator layer, the reservoir carrier, the blocking layer, the covering layer, the protective layer, yand the adhesive, in the composition of the transporting liquid or vehicle, in the physiologically active agents, in the mode of impregnating the active agent carrier with the physiologically active agent and the reservoir carrier with the transporting liquid or vehicle, in the mode of applying and securing the assembled unit to the skin, and the like may be made by those skilled in the art in accordance with the principles set forth herein and the claims annexed thereto.

I claim:

l. A composite unit useful for the administration of measured doses of physiologically active agents by percutaneous absorption, said unit comprising `a carrier layer of absorbent material impregnated with said active agent, a separator layer of non-absorbent, non-permeable material superposed over said carrier layer, a reservoir layer of absorbent material disposed above said separator layer, a non-permeable, non-absorbent blocking layer between said reservoir layer and said separator layer to separate said layers from each other, said blocking layer being adapted to prevent liquid from flowing from said reservoir layer to said carrier layer when intact and adapted to be moved when the unit is to be used so as to bring said reservoir layer into contact with said underlying separator layer, wick means in contact to said carrier layer, said wick means being adapted to be brought into communication with said reservoir layer when said blocking layer is moved, said reservoir layer being charged with a transporting iiuid for said active agent, and a cover layer superposed over said reservoir layer and adapted to prevent evaporation of said transporting uid.

2. The composite package according to claim 1, wherein the cover layer is provided at its borders with an adhesive flayer adapted to secure the unit preparation to the skin when in use.

3. The composite package according to claim 1, whereing pipette means are provided for applying said transporting liquid to said reservoir layer.

4. 'Ihe composite package according to claim 1, wherein said composite package is vprovided with a protective layer adjacent to the carrier layer, said protective layer being adapted to be removed before use and application of said composite package to the skin.

5. The composite unit according to claim 1, wherein the separator layer, the blocking layer, and the cover layer consist of non-absorbent non-permeable plastic material.

6i. A composite unit for the administration of a measured dose of a physiologically active agent by percutaneous absorption, which unit comprises a carrier layer of absorbent material capable of retaining a measured dose of said active agent and carrying said measured dose, a separator layer of non-absorbent, non-permeable material superposed over said carrier layer, a reservoir layer composed of absorbent material disposed above said separator layer, a liquid vehicle for said active agent, the -absorbent material of the reservoir layer being impregnated with said liquid vehicle, and wick means between the reservoir layer and the carrier layer and bypassing the separator layer to place the reservoir layer in communication with added to the same dose of procaine, i.e. 1 mg. per sq. cm. 75 the carrier layer, the cross-sectional area of the wick References Cited in the le of this patent UNITED STATES PATENTS Shepherd Nov. 30, 1926 Krusi Mar. 12, 1929 Prisk July 17, 1951 Winsten July 31, 1951 Lustig Jan. 18, 1955 

1. A COMPOSITE UNIT USEFUL FOR THE ADMINISTRATION OF MEASURED DOSES OF PHYSIOLOGICALLY ACITVE AGENTS BY PERCUTANEOUS ABSORPTION, SAID UNIT COMPRISING A CARRIER LAYER OF ABSORBENT MATERIAL IMPREGNATED WITH SAID ACTIVE AGENT, A SEPARATOR LAYER OF NON-ABSORBENT, NON-PERMEABLE MATERIAL SUPERPOSED OVER SAID CARRIER LAYER, A RESERVOIR LAYER OF ABSORBENT MATERIAL DISPOSED ABOVE SAID SEPARATOR LAYER, A NON-PERMEABLE, NON-ABSORBENT BLOCKING LAYER BETWEEN SAID RESERVOIR LAYER AND SAID SEPARATOR LAYER TO SEPARATE SAID LAYERS FROM EACH OTHER, SAID BLOCKING LAYER BEING ADAPTED TO PREVENT LIQUID FROM FLOWING FROM AID RESERVOIR LAYER TO SAID CARRIER LAYER WHEN INTACT AND ADAPTED TO BE MOVED WHEN THE UNIT IS TO BE USED SO AS TO BRING SAID RESERVOIR LAYER INTO CONTACT WITH SAID UNDERLYING SEPARATOR LAYER, WICK MEANS IN CONTACT TO SAID CARRIER LAYER, SAID WICK MEANS BEING ADAPTED TO BE BROUGHT INTO COMMUNICATION WITH SAID RESERVOIR LAYER WHEN SAID BLOCKING LAYER IS MOVED, SAID RESERVOIR LAYER BEING CHARGED WITH A TRANSPORTING FLUID FOR SAID ACTIVE AGENT, AND A COVER LAYER SUPERPOSED OVER SAID RESERVOIR LAYER AND ADAPTED TO PREVENT EVAPORATION OF SAID TRANSPORTING FLUID. 